Background: Both genes and environment play a role in depressive disorders. While a dysregulation of the monoaminergic systems may be sufficient to cause depression, a growing body of data indicates that other endogenous compounds, such as neuropeptides, as well as hippocampal cell loss/neurogenesis may be important in pathophysiology and treatment of depression. With regard to treatment, it is not clear whether early intervention could alleviate or prevent the disorder. Consequently, we studied neuropeptides in I. CSF from depressed inpatients before and after citalopram treatment, and II. brains of animal models: (i) genetic - the Flinders Sensitive Line (FSL) rat and their controls, the FRL line, (ii) environmental - early maternal separation that mimics early life trauma in humans, experiences that predict adult life psychopathology.Method: In human studies, CSF was collected before and after 5 weeks of citalopram treatment. In animals, early life maternal separation was superimposed on the FSL and FRL rats and behavior studied when the animals reached adulthood, and brain neurochemistry and cell proliferation post-mortem. On postnatal days (PND) 2−14, FSL and FRL pups were maternally separated. Escitalopram or vehicle in food were started on PND 44. Porsolt swim test was done on PND 64−65.Results: In patients, CRH was decreased and NPY increased following successful citalopram treatment. Strong correlations between CRH decrease, NPY increase and clinical outcome were found. In animals, baseline FSL-FRL differences were found in the Porsolt swim test and in brain neuropeptides, in particular NPY and CGRP in selected brain regions. Cell proliferation was also affected. Moreover, maternal separation and escitalopram also differentiated between the strains.Conclusions: Both genes and environment play a role in depression but the consequences of early life events are more deleterious in genetically vulnerable individuals. NPY and CRH as well as cell proliferation changes appear to constitute biological correlates of depression and may be markers of treatment. Lastly, results from our animal studies raise a question whether early drug intervention should be explored as a potential strategy to alleviate adult life psychopathology.